Musculo-skeletal abnormalities represent common complications of end-stage renal failure. The role of aluminum in the pathogenesis of these abnormalities is not well understood. In addition, little is known about the effect of 1,25 Vit. D3 and/or parathyroid hormone (PTH) on aluminum accumulation in uremic muscle and bone. The proposed study is designed to evaluate these questions which represent the major unresolved problems of uremic osteodystrophy and myopathy. Experimental uremia will be induced in dogs by 5/6 nephrectomy and uremic bone and muscle abnormalities will be allowed to develop for 3 months. Bone and muscle will be studied before and after 3 months of uremia. Thereafter, dogs will be parathyroidectomized and PTH and/or 1,25 Vit. D3 will be given in combinations known to exist in treated and untreated patients with renal failure. In addition, aluminum will be administered to all dogs for 2 months followed by therapy with the chelating agent desferrioxamine for 4 months. Bone and muscle biopsies will be repeated after aluminum administration and after therapy with desferrioxamine. The following studies will be performed in all tissue samples: measurement of aluminum in muscle and bone, microscopic and ultrastructural localization of aluminum in bone by histochemical staining and by energy dispersive X-ray analysis of bone, histoenzymology of muscle fibers, and calcium transport kinetics of the sarcoplasmic reticulum. Serum levels of 1,25 Vit. D3, PTH and serum concentrations of calcium, phosphate, alkaline phosphatase, and aluminum will be followed throughout the study. The results should provide information on the effects of aluminum on muscle and bone in renal failure and the contribution of parathyroid hormone and 1,25 Vit. D3 to these effects. In addition, therapeutic modalities such as desferrioxamine, 1,25 Vit. D3 and parathyroidectomy will be examined. The questions addressed by the experiments are of considerable importance for the understanding and management of musculo-skeletal abnormalities in uremia and the answers should provide a solid base for prophylaxis and therapy of these abnormalities.